From 2020 to 2023, South Dakota witnessed a substantial increase in cases of congenital syphilis (CS), with the highest rates identified in rural and Native American (NA) communities. Here, we discuss 3 severe cases of CS in premature infants born to NA individuals and communities in South Dakota with poor access to prenatal care. The infants in these 3 cases presented with varying clinical conditions, including respiratory failure, persistent pulmonary hypertension of the newborn, severe direct hyperbilirubinemia, feeding intolerance, and necrotizing enterocolitis. Lack of prenatal care and other systemic health disparities likely contributed to the increased disease burden. For NA communities, rurality, limited resources, systemic racism, historical trauma, and lack of trust in medical institutions likely contribute to inadequate prenatal care. All 3 of these cases also occurred in pregnant people with a present or history of substance use disorders, which may have led to further hesitancy to seek care because of fear of prosecution. To combat the rising number of syphilis and CS cases, we advocate for new and continued outreach that provides education about and testing for sexually transmitted diseases to NA and rural populations, increased care coordination, the integration of point-of-care testing and treatment strategies in lower resource centers, and legislative allocation of additional resources to engage pregnant people with or at risk for substance use disorders.